Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:22][N:11]2[CH2:12][CH2:13][N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:15][CH:10]2[CH2:9][CH2:8]1)(=O)=O.[C-:23]#[N:24].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[N:14]1[CH2:13][CH2:12][N:11]2[CH2:22][CH:7]([CH2:6][C:23]#[N:24])[CH2:8][CH2:9][CH:10]2[CH2:15]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1CCC2CN(c3ncccn3)CCN2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1CCC2CN(c3ncccn3)CCN2C1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 38.1 g (117 mmol) of (7SR,9aSR)-7-(methanesulfonyloxy)methyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (prepared according to U.S. Pat. No. 5,122,525) and 6.01 g (122 mmol) of sodium cyanide in 500 mL of dry DMF was heated at 110° C. for 16 h. The mixture was cooled to room temperature, 10 mL of saturatic sodium bicarbonate was added and the mixture concentrated in vacuo. Water (1000 mL) and ethyl acetate (1000 mL) were added to the solid residue, the pH was adjusted to 11, and the layers were separated. The organic phase was washed with water (2×), dried (sodium sulfate), filtered and evaporated. Recrystalization from ethyl acetate-hexane gave 14.5 g of [(7SR,9aSR)-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-yl]acetonitrile. 13C NMR (CDCl3): d 19.5, 24.1, 26.9, 31.3, 33.1, 43.6, 48.9, 54.5, 109.8, 119.8, 157.7, 161.4.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=S>>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:5][C:18]=1[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: NCc1ccccc1N
Reactant: Cc1ccccc1N=C=S
Product: Cc1ccccc1NC1=Nc2ccccc2CN1

Procedure:
The title compound (MS: m/e=238.3 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 2-methylphenylisothiocyanate.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[CH2:7][C:5]=2[N:6]=1.CC[N:15](C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[S:3][C:4]2[N:9]=[C:8]([C:10]([NH2:15])=[O:12])[CH2:7][C:5]=2[N:6]=1
Reactant: O=C(O)C1=Nc2sc(Br)nc2C1
Reactant: CCN(C(C)C)C(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)C1=Nc2sc(Br)nc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Add to a solution of 2-bromo-6H-pyrrolo[3,2-d]thiazole-5-carboxylic acid (2.53 gm, 10 mmol) in DMF (45 ml), DIEA (diisopropylethylamine, 10 ml, 6 eq), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl, 5.0 gm, 3.5 eq); HOBT (1-hydroxybenzotriazole, 1.91 gm, 14 mmol, 1.4 eq) and NH4Cl (2.25 gm, 42.0 mmol). Stir the mixture at room temp for 6 hr and monitor by LC-MS. When complete, dilute the mixture with ethyl acetate, and wash with water and brine. Collect the solid by filtration (2.21 gm) and purify by chromatography on silica gel (ISCO silica cartridge, 4 gm, elute with methanol (10-40%) in methylene chloride) to afford the title compound (550 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[C:4]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:8][CH2:7][N:6]2[CH:21]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:41])[CH:38]([CH3:40])[CH3:39].S([O-])(O)(=O)=O.[K+]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:4]1[C:3](=[O:30])[C:2]([NH:1][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])=[CH:21][N:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[C:10](=[O:11])[C:5]=12)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (29 mg) in chloroform (0.6 ml) were added pyridine (0.0082 ml) and isobutyryl chloride (0.01 ml) at 0° C., and the mixture was stirred at room temperature for 1.5 hr. 5% Aqueous potassium hydrogen sulfate solution was added and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was dried, concentrated and purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give N-[9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide (29 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[CH:8]=2)[CH2:3]1.[CH:17](OCC)=[O:18]>C(Cl)(Cl)Cl>[CH:17]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11][C:12](=[O:16])[N:13]([CH3:14])[CH3:15])[CH:8]=2)[CH2:3]1)=[O:18]
Reactant: CCOC=O
Reactant: CN(C)C(=O)Sc1ccc2c(c1)CC(N)C2
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Sc1ccc2c(c1)CC(NC=O)C2
Temperature: 55 °C
Yield: 35 %

Procedure:
To dimethylthiocarbamic acid-S-[2-aminoindan-5-yl) ester (2.0 g; 8.46 mmol) in CHCl3 (10 mL) is added ethyl formate (50 mL) and the reaction heated at 55° C. for 24 h. The reaction is cooled, the solvent removed under reduced pressure, and the crude oil purified by flash chromatography (SiO2) eluting with an ethyl acetate-methanol gradient to afford 0.77 g (35%) of dimethylthiocarbamic acid-S-(2-formylaminoindan-5-yl)ester as a white solid.
Reaction SMILES: [CH2:1]1[O:15][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][CH:13]=[CH2:14])([CH3:5])[O:3][CH2:2]1.[CH:16]1[C:21]([C:22](OO)=O)=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OOC(=O)C1C=CC=CC=1)(=[O:33])C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]1[CH2:2][O:3][C:4]([C:6]23[O:33][C:7]2([CH2:12][CH:13]=[CH:14][CH2:22][C:21]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=[CH:11]3)([CH3:5])[O:15]1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: C=CCc1ccccc1C1(C)OCCO1
Reactant: O=C(OO)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C23C=CC=CC2(CC=CCc2ccccc2)O3)OCCO1
Reaction time: 192 h

Procedure:
The mixture of 1 g of o-allylacetophenone ethylene ketal, perbenzoic acid prepared from 3.6 g of benzoylperoxide and 100 ml of chloroform was allowed to stand at 5° C for 8 days. The resulting mixture was washed with 10% sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain o-(α,α-ethylenedioxyethyl) benzylallylbenzene oxide as pale brownish oily substance.
Reaction SMILES: C(Cl)(Cl)Cl.C(O)(=O)C.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10]1.C1C(=O)N([Br:27])C(=O)C1>O>[Br:27][C:10]1[S:9][CH:13]=[CH:12][C:11]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccsc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
In a 250 ml 3-neck flask containing 50 ml of CHCl3 and 50 ml of glacial acetic acid, 9.5 grams (0.0558 mol) of ethyl thiophene-3-acetate was added, followed by 9.93 grams (0.0558 mol) of NBS. The mixture was stirred at room temperature for 12 hours. The mixture became clear yellow solution after 1 hour and then was cooled down to room temperature, and poured into 200 ml deionized (DI) water. The organic portion was washed again with 100 ml of DI-water, and then finally washed with 100 ml of 5% aqueous sodium bicarbonate solution. After having been dried over magnesium sulfate, the solvent was filtered and the product was concentrated under vacuum. The resulting residue was vacuum distilled at 95° C. under 1 mm mercury (Hg) yielding 12.3 grams of ethyl 2-bromothiophene-3-acetate (88% yield). 1H NMR (CDCl3): 1.26 (t, 3H), 3.60 (s, 2H), 4.16 (q, 2H), 6.93 (d, 1H), 7.22 (d, 1H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]([F:28])([O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18].[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:15][C:16]([F:28])([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)[CH:17]([F:18])[F:19].[F:15][C:16]([F:28])([O:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH:30]2[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]2)=[CH:25][CH:26]=1)[CH:17]([F:18])[F:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(OC(F)(F)C(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)C(F)F)cc2)CC1
Product: FC(F)C(F)(F)Oc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 176.3 %

Procedure:
4-[4-(1,1,2,2-tetrafluoroethoxy)phenoxy]piperidine was prepared as follows: Diisopropyl azodicarboxylate (2.25 mL) was added to a solution of 4-(1,1,2,2-tetrafluoroethoxy)phenol (2.0 g), tert-butyl 4 hydroxypiperidine-1-carboxylate (2.3 g) and triphenylphosphine (3.5 g) in dichloromethane (30 mL). The reaction mixture was stirred at ambient temperature for 18 hours and then concentrated at reduced pressure. This resulting mixture was purified by silica column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexane to give the tert-butyl 4-[4-(1,1,2,2-tetrafluoroethoxy)phenoxy]piperidine-1-carboxylate as a light green oil (3.3 g); NMR Spectrum: (DMSOd6) 1.39 (s, 9H), 1.43-1.57 (m, 2H), 1.82-1.95 (m, 2H), 3.09-3.24 (m, 2H), 3.56-3.70 (m, 2H), 4.47-4.59 (m, 1H), 6.73 (tt, 1H), 7.03 (d, 2H), 7.16 (d, 2H).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([CH3:20])([N:12]2[CH:16]=[C:15]([N+:17]([O-])=O)[N:14]=[CH:13]2)[CH3:11])[CH2:3]1.[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][C@@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](O)=[O:35])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][C@@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([NH:17][C:15]2[N:14]=[CH:13][N:12]([C:10]([CH3:20])([CH3:11])[CH2:9][N:4]3[CH2:3][C@@H:2]([CH3:1])[O:7][C@@H:6]([CH3:8])[CH2:5]3)[CH:16]=2)=[O:35])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CC1CN(CC(C)(C)n2cnc([N+](=O)[O-])c2)CC(C)O1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1ccccc1
Product: C[C@@H]1CN(CC(C)(C)n2cnc(NC(=O)[C@@H](NC(=O)Cc3cc(F)cc(F)c3)c3ccccc3)c2)C[C@H](C)O1

Procedure:
2,6-Dimethyl-4-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-morpholine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic acid to afford the title compound: MS 540 m/z (M+1).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OC(=O)NC1C=CC=C(C=O)C=1)(C)(C)C.[CH3:43][C:44]([NH:48]C(C1CCNCC1)=O)([CH3:47])[CH2:45][CH3:46]>>[CH3:43][C:44]([NH:48][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH2:10][CH2:11]1)=[O:5])([CH3:47])[CH2:45][CH3:46]
Reactant: CCC(C)(C)NC(=O)C1CCNCC1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Agent: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Product: CCC(C)(C)NC(=O)C1CCN(Cc2cccc(N)c2)CC1

Procedure:
The title compound is prepared according to the reaction 1.001a and 1.001d described above using (3-formyl-phenyl)-carbamic acid tert-butyl ester and piperidine-4-carboxylic acid (1,1-dimethyl-propyl)-amide: LC-MS A: tR=0.48 min; [M+H]+=304.23.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]([OH:17])=O.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:23]1([NH:22][C:15](=[O:17])[CH2:14][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[S:6][C:2]=2[Br:1])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Br
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cc1nc(-c2ccc(Cl)cc2)sc1Br)Nc1ccccc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A mixture of 5-bromo-2-(4-chlorophenyl)thiazol-4-yl-acetic acid (1 g, 3 mmol), thionyl chloride (2 equiv., 0.72 g, 6 mmol), and chloroform were heated under reflux for 2.5 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was dissolved in CHCl3 (dry), followed by dropwise addition of aniline (2 equiv., 0.56 g, 6 mmol) and the resulting mixture refluxed for a further 5 hours. The reaction mixture cooled to room temperature and the precipitate was collected by filtration. The filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc, and filtered to yield the desired product (0.4 g, 32%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:15])[CH:16]=[C:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4-tert-Butylcyclohexanone (8.62 g, 56 mmol) was dissolved in toluene (200 ml). Methoxycarbonylmethylenetriphenylphosphorane (56.1 g, 168 mmol) was added with stirring and the reaction mixture was heated under reflux for 3 days. The solvent was removed in vacua. The residue was dissolved in hot hexanes (100 ml) and cooled to room temperature. The precipitate was filtered off and the filtrate was evaporated in vacuo to afford a yellow oil which was then purified by chromatography (silica gel, hexane/ethyl acetate, 2:1 as eluant) to give the title compound as an oil (10.78 g, 92%). 1H-NMR; δ (CDCl3) 5.60 (1H, s), 3.87 (1H, m), 3.69 (3H, s), 2.38-2.10 (2H, m), 2.03-1.77 (3H, m), 1.36-1.02 (3H, m) and 0.87 (9H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:35](=[O:36])[N:12]2[C:13]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])=[C:14](OS(C)(=O)=O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.[N-:42]=[N+:43]=[N-:44].[Na+].II>C1(C)C=CC=CC=1.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:35](=[O:36])[N:12]2[C:13]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])=[C:14]([N:42]=[N+:43]=[N-:44])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: II
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.554 g. of p-nitrobenzyl 7β-(2-thienylacetamido)-3-methylsulfonyloxy-3-cephem-4-carboxylate in 10 ml. of DMF was added one molar equivalent (0.065 g.) of sodium azide and the mixture stirred at room temperature for 30 minutes. The mixture was transferred to a separatory funnel with ethyl acetate and the solution was washed three times with water, once with brine, dried over sodium sulfate and evaporated to dryness. The product, 0.523 g, obtained as a yellow froth showed a single spot on silica gel thin layer chromatography using 1:1, ethyl acetate:toluene for development and iodine for visualization.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.CON(C)[C:18](=[O:21])[CH2:19][CH3:20].[Cl-].[NH4+]>CCOCC.O.C(OCC)(=O)C>[S:6]1[C:10]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: c1ccc2sccc2c1
Reactant: CCC(=O)N(C)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(=O)c1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes; 28.9 ml) was added dropwise under nitrogen at 0° C. to a stirred solution of benzo[b]thiophene (6.21 g) in ether (90 ml), then the mixture was stirred 0° C. for 15 minutes and cooled to −70° C. A solution of N-methoxy-N-methylpropionamide (5.42 g) in ether (40 ml) was added over 10 minutes, then the mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 3.5 hours. The mixture was poured into saturated aqueous ammonium chloride solution (200 ml) and ethyl acetate (100 ml) and water (50 ml) were added. The organic phase was separated, washed with saturated aqueous sodium chloride solution (150 ml), dried (Na2SO4) and the solvents were removed in vacua. The residue was triturated with petroleum ether (b.p. 40-60° C.) (25 ml) and the resulting solid was collected by filtration and dried in vacuo to give 1-(benzo[b]thiophen-2-yl)propan-1-one (7.05 g) as a colourless solid, m.p. 79-81° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=O)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1.P(Cl)(Cl)(Cl)=O.CO/N=C1/C2C(C)=NC(N)=NC=2C[C@@H](C2C=CC(F)=CC=2C2C(F)=NC=CC=2)C/1>C(#N)C>[N:22]1([C:11]2[C:5]3[C:4]([CH3:21])=[N:3][C:2]([NH2:1])=[N:7][C:6]=3[CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[N:10]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: Cc1nc(N)nc2c1C(=O)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: c1ccc2[nH]nnc2c1
Agent: CO/N=C1\C[C@H](c2ccc(F)cc2-c2cccnc2F)Cc2nc(N)nc(C)c21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nc(N)nc2c1C(n1nnc3ccccc31)=N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 75 °C

Procedure:
In a 2-neck round-bottomed flask, under a blanket of nitrogen was added (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (106a, 1.00 g, 2.85 mmol), 1H-benzo[d][1,2,3]triazole (106b, 0.678 g, 5.70 mmol) and anhydrous acetonitrile (14 mL). Phosphoryl trichloride (0.796 mL, 8.54 mmol) was added slowly to the mixture and the reaction was heated in 75° C. oil bath for 18 hours. By LC/MS about 7-10% of compound 1 remained unreacted. The reaction mixture was concentrated, then diluted with 80 mL of ethyl acetate and the resulting mixture was added slowly to 40 mL of saturated sodium bicarbonate. The layers were partitioned. The aqueous layer was washed one more time with 40 mL of ethyl acetate. The organic layers combined, washed with brine, dried over sodium sulfate, and concentrated to a yellow-light brown solid, 1.72 g, contained about 0.37 g of excess benzotriazole. The crude material was taken on to the next step without purification. MS (ES) [M+H] calc'd for C20H15BrFN7, 452. found, 452.3-454.3. 1H NMR (400 MHz, CHLOROFORM-d) 61.96 (s, 3H), 2.74 (dd, J=16.42, 14.91 Hz, 1H), 3.13 (dd, J=16.55, 4.17 Hz, 1H), 5.20 (dd, J=14.91, 4.04 Hz, 1H), 5.69 (s, 2H), 7.03-7.12 (m, 1H), 7.38 (dd, J=8.21, 2.65 Hz, 1H), 7.47-7.52 (m, 1H), 7.56-7.63 (m, 1H), 7.74 (dd, J=8.84, 6.06 Hz, 1H), 8.16 (d, J=9.35 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[C:4]([C:16](OCC)=[O:17])=[N:3]1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.C1CCCCC1>[OH:17][CH2:16][C:4]1[C:5]([C:12]([F:13])([F:14])[F:15])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1nn(C)c(C(=O)OCC)c1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)c(CO)nn1C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A solution of 6.00 g (20.4 mmol) of diethyl 1-methyl-4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate in 80 ml of tetrahydrofuran is admixed under argon at −78° C. with 38.9 ml (42.8 mmol) of a 1.1M solution of diisobutylaluminium hydride in cyclohexane and stirred overnight at this temperature. The reaction mixture is admixed with water and extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate, filtered over silica gel and concentrated by evaporation in vacuo. Chromatographic purification on silica gel gives 4.10 g of ethyl 3-(hydroxymethyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (80%).
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[N:24]=[CH:23][C:22]=1[C:36]([NH:38][C:39]1[CH:40]=[N:41][C:42]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:43]([CH3:45])[CH:44]=1)=[O:37].O>ClCCl>[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][N:27]=2)[N:24]=[CH:23][C:22]=1[C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42]([CH:46]2[CH2:51][CH2:50][N:49]([CH:3]3[CH2:2][O:1][CH2:4]3)[CH2:48][CH2:47]2)=[N:41][CH:40]=1)=[O:37]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C2COC2)CC1
Reaction time: 5 h
Yield: 35.5 %

Procedure:
3-Oxetanone (121 mg) and sodium triacetoxyborohydride (143 mg) were added at room temperature to a solution of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (250 mg) described in Reference Example 171 in dichloromethane (24 ml), and stirred at the same temperature for five hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate and concentrated. 1N Aqueous solution of sodium hydroxide (20 ml) was added to the resulting residue, solid was collected by filtration purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (100 mg) as a white solid.
Reaction SMILES: C(N1CC[C:12](=[O:15])[CH2:11][CH2:10]1)CC1C=CC=CC=1.NC1C=C(O)C=CC=1.[CH2:24]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]2[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:33]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(=O)CC)(=O)CC.CN(C1C=CC=CN=1)C>C(N(CC)CC)C>[OH:45][C:41]1[CH:40]=[C:39]([N:38]([CH:35]2[CH2:34][CH2:33][N:32]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:37][CH2:36]2)[C:12](=[O:15])[CH2:11][CH3:10])[CH:44]=[CH:43][CH:42]=1
Reactant: Oc1cccc(NC2CCN(CCc3ccccc3)CC2)c1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: CCC(=O)OC(=O)CC
Agent: CN(C)c1ccccn1
Agent: Nc1cccc(O)c1
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1cccc(O)c1)C1CCN(CCc2ccccc2)CC1

Procedure:
As indicated in Scheme II-D above, the desired mPEGn-O-fentanyl conjugates were prepared by first reacting 1-phenethylpiperidin-4-one with 3-aminophenol under reducing conditions to thereby convert the keto functionality into an amine, i.e., by reaction with the amino group of 3-aminophenol. The product, 3-(1-phenethylpiperidin-4-ylamino)phenol, was then reacted with propionic anhydride in the presence of base (e.g., triethyl amine) and dimethylaminopyridine (DMAP) under conditions effective to form N-(3-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide. Finally, introduction of the oligomeric PEG functionality was carried out by reacting the precursor, N-(3-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide, with a molar excess of mPEGoligotosylate under coupling conditions effective to form the desired conjugates. Ratios of reactants and reaction conditions generally employed are provided in the reaction schemes above.